Provided are composition and methods for treating radiation-induced cell damage, and in particular aspects to methods for protecting, mitigating or otherwise treating radiation-induced induced depletion of tissue stem cells and injury to the supportive stem cell niche, and in even more particular aspects to methods for protecting, mitigating or otherwise treating radiation-induced gastrointestinal syndrome (RIGS), comprising sequential administration of a Wnt pathway activator/agonist (e.g., Rspo1 or a small molecule inducer thereof) that amplifies the surviving intestinal stem cell (ISC) pool post-radiation exposure, followed by a selective antagonist of the β-Catenin-CBP interaction (e.g., ICG-001 or other exemplary compounds disclosed herein) that accelerates differentiation of the stimulated (e.g., Rspo1-stimulated) ISC in crypt-villi axis, promoting villous regeneration and intestinal restitution, thereby mitigating RIGS. Adjunctive and combination therapy embodiments are encompassed.